rs1218889799

Variant names:

• chr9-132897596-C-A
• rs1218889799
• NM_000368.5:c.2640G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-132897596-C-A
• chr9-132897596-C-T
• chr9-132897596-C-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000368.5(TSC1):​c.2640G>T​(p.Met880Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M880T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000016 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 2.29
• Publications: 3 publications found

Genes affected

TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

TSC1 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
• lung lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22614953).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000368.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	NM_000368.5	MANE Select	c.2640G>T	p.Met880Ile	missense	Exon 21 of 23	NP_000359.1	Q92574-1
	TSC1	NM_001406592.1		c.2640G>T	p.Met880Ile	missense	Exon 21 of 23	NP_001393521.1	X5D9D2
	TSC1	NM_001406593.1		c.2640G>T	p.Met880Ile	missense	Exon 21 of 23	NP_001393522.1	Q92574-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC1	ENST00000298552.9	TSL:1 MANE Select	c.2640G>T	p.Met880Ile	missense	Exon 21 of 23	ENSP00000298552.3	Q92574-1
	TSC1	ENST00000490179.4	TSL:3	c.2640G>T	p.Met880Ile	missense	Exon 22 of 24	ENSP00000495533.2	Q92574-1
	TSC1	ENST00000643875.1		c.2640G>T	p.Met880Ile	missense	Exon 21 of 23	ENSP00000495158.1	Q92574-1

Frequencies

GnomAD3 genomes AF: 0.0000164 AC: 2 AN: 122104 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000215

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000164

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000129 AC: 13 AN: 1009114 Hom.: 0 Cov.: 37 AF XY: 0.0000117 AC XY: 6 AN XY: 511604

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000411 AC: 1 AN: 24316

American (AMR) AF: 0.00 AC: 0 AN: 33866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18184

East Asian (EAS) AF: 0.00 AC: 0 AN: 27436

South Asian (SAS) AF: 0.00 AC: 0 AN: 70726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4356

European-Non Finnish (NFE) AF: 0.0000147 AC: 11 AN: 750344

Other (OTH) AF: 0.0000245 AC: 1 AN: 40876

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000164 AC: 2 AN: 122170 Hom.: 0 Cov.: 29 AF XY: 0.0000176 AC XY: 1 AN XY: 56818

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33562

American (AMR) AF: 0.00 AC: 0 AN: 10234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3198

East Asian (EAS) AF: 0.00 AC: 0 AN: 3628

South Asian (SAS) AF: 0.00 AC: 0 AN: 3258

European-Finnish (FIN) AF: 0.000215 AC: 1 AN: 4652

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 182

European-Non Finnish (NFE) AF: 0.0000164 AC: 1 AN: 60962

Other (OTH) AF: 0.00 AC: 0 AN: 1666

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000359 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Tuberous sclerosis 1 (3)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1854465:Tuberous sclerosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.0092	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	0.019
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.76	N
PhyloP100		2.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.13	N
REVEL	Uncertain	0.30
Sift	Benign	0.25	T
Sift4G	Benign	0.13	T
Polyphen		0.083	B
Vest4		0.47
MutPred		0.26		Loss of disorder (P = 0.05)
MVP		0.30
MPC		0.56
ClinPred		0.69	D
GERP RS		5.8
Varity_R		0.31
gMVP		0.21
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1218889799; hg19: chr9-135772983; COSMIC: COSV109425223;